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The copper metabolism disorder Wilson's disease was first defined in 1912. Wilson's disease can present with hepatic and neurological deficits, including dystonia and parkinsonism. Early-onset presentations in infancy and late-onset manifestations in adults older than 70 years of age are now well recognised. Direct genetic testing for ATP7B mutations are increasingly available to confirm the clinical diagnosis of Wilson's disease, and results from biochemical and genetic prevalence studies suggest that Wilson's disease might be much more common than previously estimated. Early diagnosis of Wilson's disease is crucial to ensure that patients can be started on adequate treatment, but uncertainty remains about the best possible choice of medication. Furthermore, Wilson's disease needs to be differentiated from other conditions that also present clinically with hepatolenticular degeneration or share biochemical abnormalities with Wilson's disease, such as reduced serum ceruloplasmin concentrations. Disordered copper metabolism is also associated with other neurological conditions, including a subtype of axonal neuropathy due to ATP7A mutations and the late-onset neurodegenerative disorders Alzheimer's disease and Parkinson's disease.

Wilson’s disease is an autosomal–recessive disorder of copper metabolism caused by mutations in ATP7B and associated with neurological, psychiatric, ophthalmological and hepatic manifestations. Decoppering treatments are used to prevent disease progression and reduce symptoms, but neurological outcomes remain mixed. In this article, we review the current understanding of pathogenesis, biomarkers and treatments for Wilson’s disease from the neurological perspective, with a focus on recent advances. The genetic and molecular mechanisms associated with ATP7B dysfunction have been well characterised, but despite extensive efforts to identify genotype–phenotype correlations, the reason why only some patients develop neurological or psychiatric features remains unclear. We discuss pathological processes through which copper accumulation leads to neurodegeneration, such as mitochondrial dysfunction, the role of brain iron metabolism and the broader concept of selective neuronal vulnerability in Wilson’s disease. Delayed diagnoses continue to be a major problem for patients with neurological presentations. We highlight limitations in our current approach to making a diagnosis and novel diagnostic biomarkers, including the potential for newborn screening programmes. We describe recent progress in developing imaging and wet (fluid) biomarkers for neurological involvement, including findings from quantitative MRI and other neuroimaging studies, and the development of a semiquantitative scoring system for assessing radiological severity. Finally, we cover the use of established and novel chelating agents, paradoxical neurological worsening, and progress developing targeted molecular and gene therapy for Wilson’s disease, before discussing future directions for translational research.

Copper is one of the most abundant basic transition metals in the human body. It takes part in oxygen metabolism, collagen synthesis, and skin pigmentation, maintaining the integrity of blood vessels, as well as in iron homeostasis, antioxidant defense, and neurotransmitter synthesis. It may also be involved in cell signaling and may participate in modulation of membrane receptor-ligand interactions, control of kinase and related phosphatase functions, as well as many cellular pathways. Its role is also important in controlling gene expression in the nucleus. In the nervous system in particular, copper is involved in myelination, and by modulating synaptic activity as well as excitotoxic cell death and signaling cascades induced by neurotrophic factors, copper is important for various neuronal functions. Current data suggest that both excess copper levels and copper deficiency can be harmful, and careful homeostatic control is important. This knowledge opens up an important new area for potential therapeutic interventions based on copper supplementation or removal in neurodegenerative diseases including Wilson’s disease (WD), Menkes disease (MD), Alzheimer’s disease (AD), Parkinson’s disease (PD), and others. However, much remains to be discovered, in particular, how to regulate copper homeostasis to prevent neurodegeneration, when to chelate copper, and when to supplement it.

Patients with Wilson’s disease, an autosomal recessive disorder caused by ATP7B mutations, present with hepatic and neurological symptoms, including tremors, chorea, personality changes, and rare manifestations such as neuropathy, autonomic dysfunction, headache, and epilepsy. This report describes the case of a 14-year-old man born to consanguineous parents who presented with focal seizures and oromandibular dystonia. A neurological exam revealed left upper limb hypotonia. An electroencephalogram showed right hemisphere epileptiform activity, and magnetic resonance imaging indicated bilateral basal ganglia hyperintensities. An ophthalmological exam revealed an incomplete Kayser–Fleischer ring. Laboratory tests confirmed Wilson’s disease with low serum ceruloplasmin (3 mg/dL) and elevated urinary copper excretion (1226 mcg/24 h) levels. Treatment included penicillamine (250 mg/day) and zinc (50 mg bi-daily), along with clonazepam for seizures. Routine follow-ups were recommended. This case highlights the importance of recognizing neurological presentations in patients with Wilson’s disease for timely diagnosis and management.

Clinicians are required to assess abnormal liver chemistries on a daily basis. The most common liver chemistries ordered are serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and bilirubin. These tests should be termed liver chemistries or liver tests. Hepatocellular injury is defined as disproportionate elevation of AST and ALT levels compared with alkaline phosphatase levels. Cholestatic injury is defined as disproportionate elevation of alkaline phosphatase level as compared with AST and ALT levels. The majority of bilirubin circulates as unconjugated bilirubin and an elevated conjugated bilirubin implies hepatocellular disease or cholestasis. Multiple studies have demonstrated that the presence of an elevated ALT has been associated with increased liver-related mortality. A true healthy normal ALT level ranges from 29 to 33 IU/l for males, 19 to 25 IU/l for females and levels above this should be assessed. The degree of elevation of ALT and or AST in the clinical setting helps guide the evaluation. The evaluation of hepatocellular injury includes testing for viral hepatitis A, B, and C, assessment for nonalcoholic fatty liver disease and alcoholic liver disease, screening for hereditary hemochromatosis, autoimmune hepatitis, Wilson's disease, and alpha-1 antitrypsin deficiency. In addition, a history of prescribed and over-the-counter medicines should be sought. For the evaluation of an alkaline phosphatase elevation determined to be of hepatic origin, testing for primary biliary cholangitis and primary sclerosing cholangitis should be undertaken. Total bilirubin elevation can occur in either cholestatic or hepatocellular diseases. Elevated total serum bilirubin levels should be fractionated to direct and indirect bilirubin fractions and an elevated serum conjugated bilirubin implies hepatocellular disease or biliary obstruction in most settings. A liver biopsy may be considered when serologic testing and imaging fails to elucidate a diagnosis, to stage a condition, or when multiple diagnoses are possible.

Wilson disease (WD) is an inherited disorder caused by ATP7B mutations, resulting in toxic copper accumulation primarily in the liver and brain. While copper‐induced hepatotoxicity is a hallmark of WD, the mechanisms linking copper overload to liver injury remain unclear. This study aimed to investigate the role of cuproptosis, a copper‐dependent form of regulated cell death, in WD pathogenesis and identify key cuproptosis‐related genes (CRGs). We utilised ATP7B−/− mice and HepG2 cells to model WD. Liver injury was assessed histologically and biochemically. Transcriptomic analysis identified differentially expressed CRGs, followed by machine learning (LASSO, SVM‐RFE) to identify key genes. Functional enrichment and protein validation were performed. Candidate biomarkers were evaluated in WD patient serum and confirmed in the mouse model. ATP7B−/− mice showed marked hepatocellular injury with elevated AST, ALT and LDH. Cuproptosis markers (FDX1, DLST, DLAT, LIAS) were upregulated in both liver tissue and HepG2 cells. Copper exposure decreased cell viability and increased LDH release, exacerbated by Elesclomol and alleviated by Tetrathiomolybdate. Transcriptomics revealed Lox, App, Afp, Alb, Gpc1, Gls were central hub genes. Importantly, SiRNA knockdown of Gpc1, Gls, Lox and App alleviated cuproptosis, supporting their key roles in cuproptosis. Cuproptosis plays a critical role in copper‐induced liver injury in WD. Key mediators identified include Gpc1, Gls, Lox and App, which were validated as potential therapeutic targets. These findings provide new insights into the molecular mechanisms underlying WD and may inform the development of targeted treatment strategies.

Novel therapies for Wilson disease (WD) will require appropriate biomarkers and clinically relevant endpoints to demonstrate therapeutic efficacy. We aimed to develop robust, minimally invasive biomarker assays to assess target engagement in future clinical trials for WD therapeutics. We conducted a single-center, sample collection biomarker study in 21 patients with WD and 6 control participants. Serum, liver fine needle aspiration biopsy (FNA), and liver core needle biopsy (CNB) samples were collected from participants. RNA and protein were isolated from serum exosome and biopsy samples. Samples were analyzed for mRNA expression by quantitative PCR and for protein expression by a novel electrochemiluminescence (ECL) immunoassay. ATP7B mRNA was detectable in FNA, CNB, and serum exosome samples. However, serum exosomes are not yet a viable method for ATP7B quantification. ATP7B protein was only detectable in CNB samples. We compared the FNA and CNB results for five WD patients and found mRNA expression levels to be comparable with an R 2 of 0.64 with statistical significance. The methods we developed may be useful in clinical settings to quantify hepatocyte-specific expression of ATP7B for the development of novel therapeutics for Wilson disease.

Wilson disease (WD) is a potentially treatable, inherited disorder of copper metabolism that is characterized by the pathological accumulation of copper. WD is caused by mutations in ATP7B , which encodes a transmembrane copper-transporting ATPase, leading to impaired copper homeostasis and copper overload in the liver, brain and other organs. The clinical course of WD can vary in the type and severity of symptoms, but progressive liver disease is a common feature. Patients can also present with neurological disorders and psychiatric symptoms. WD is diagnosed using diagnostic algorithms that incorporate clinical symptoms and signs, measures of copper metabolism and DNA analysis of ATP7B . Available treatments include chelation therapy and zinc salts, which reverse copper overload by different mechanisms. Additionally, liver transplantation is indicated in selected cases. New agents, such as tetrathiomolybdate salts, are currently being investigated in clinical trials, and genetic therapies are being tested in animal models. With early diagnosis and treatment, the prognosis is good; however, an important issue is diagnosing patients before the onset of serious symptoms. Advances in screening for WD may therefore bring earlier diagnosis and improvements for patients with WD. Wilson disease is an inherited disorder of copper metabolism that is characterized by the pathological accumulation of copper. This Primer describes the pathogenesis of this disorder and outlines diagnostic and management strategies.

Hepatolenticular degeneration (HLD), also known as Wilson's disease (WD), is a rare autosomal recessive disorder regarding copper metabolism. Whether gut microbiota imbalance is involved in developing HLD remains unknown. A comprehensive 16S rRNA amplicon sequencing, metagenomic sequencing, and metabonomic analysis were undertaken in patients with WD to analyze the composition and function profiles of gut microbiota in patients with WD. The data demonstrated differences in gut microbiota and metabolic pathways between WD patients and normal individuals, significantly decreasing bacterial richness and diversity. The levels of Selenomonaceae and Megamonas in WD patients are significantly higher than those in healthy individuals. The relative abundances of Roseburia inulinivorans in patients with WD are lower than in healthy individuals. Compared with healthy people, the level of metabolites in patients with WD is abnormal. Leucylproline, 5-Phenylvaleric Acid and N-Desmethylclobazam, which have nutritional and protective effects, are significantly reduced fecal metabolites in patients with WD. D-Gluconic acid, which can chelate metal ions, may be a potential treatment for WD. The positive correlation it demonstrates with Alistipes indistinctus and Prevotella stercora indicates potential bacteria able to treat WD. These metabolites are mainly related to the biosynthesis of antibiotics, alpha-linolenic acid metabolism, one carbon pool by folate, nicotinate and nicotinamide metabolism. In conclusion, the data from this study elucidate novel mechanisms describing how abnormal gut miccrobiota contribute to the pathogenesis of WD and outlines new molecules for the treatment of WD.

Copper, an indispensable trace element in living organisms, plays a pivotal role in human physiological processes. Wilson's disease (WD), an inherited disorder of copper metabolism, is caused by mutations in the ATP7B gene. This genetic malfunction disrupts the dynamics of copper transport and metabolism, thereby impairing ceruloplasmin synthesis and copper excretion. The resultant accumulation of copper in various tissues and organs precipitates a cascade of cellular demise and functional impairment. Notably, cuproptosis, a recently discovered copper-dependent regulated cell death mechanism, distinctly deviates from conventional cell death paradigms. This novel mode of cell death involves the interaction of copper with lipoacylated proteins within the tricarboxylic acid cycle, leading to proteinotoxic stress and culminating in cell death. In the realm of pathophysiology, cuproptosis has emerged as a pivotal player in a spectrum of diseases, with WD standing as a paradigm closely intertwined with the dysregulation of copper metabolism. This study aimed to encapsulate the pivotal molecular underpinnings of cuproptosis and delve into its crucial involvement in the etiopathogenesis of WD. By elucidating these mechanisms, the present analysis contributes significantly to the nuanced understanding of the pathological underpinnings of WD, thereby providing fresh insights and evidence that may direct innovative therapeutic strategies for this condition.